The ATP-sensitive, or ATP-gated potassium channels play an important role in human physiology. The ATP-sensitive potassium channel, like other potassium channels, selectively regulate the cell's permeability to potassium ions. These channels function to regulate the contraction and relaxation of the smooth muscle by opening or closing the channels in response to the modulation of receptors or potentials on the cell membrane. When ATP-sensitive potassium channels are opened, the increased permeability of the cell membrane allows more potassium ions to migrate outwardly so that the membrane potential shifts toward more negative values. Once this has occurred, the opening of the voltage-dependent calcium channels would be reduced, which in turn reduces the influx of calcium ions into the cell because the calcium channels become "increasingly less open" as the membrane potential becomes more negative. Consequently, drugs having ATP-sensitive potassium channel opening activity, drugs known as potassium channel openers, can relax vascular smooth muscle and are useful as hypotensive and coronary vasodilating agents.
A relatively large number of compounds are now known which open cell membrane ATP-sensitve potassium channels, particularly in smooth muscle: minoxidil sulfate, diazoxide and nicorandil are well known potassium channel openers. The target site for these agents is presumably on the potassium channel itself, but may also be on an associated regulatory protein. Isolation of the target site for the potassium channel openers would allow for protein sequence analysis and cloning of those potassium channel opener proteins. This would make possible new assays for molecules that interact with the potassium channel opener site.
One technique for the biochemical characterization of receptors is photoaffinity labeling using a radiolabeled photolabile molecule, or probe, which binds with high affinity to a receptor and can be irreversibly incorporated into the receptor under the influence of ultraviolet light.
In order to have an effective and useful photoaffinity probe, several requirements must be met. First, the probe must have good biological activity at the same target protein relative to the parent compounds of interest. Second, it must have a reactive group which can covalently bond to the target site upon photoactivation. Third, it must have a radioactive or fluorescent label by which the probe-target complex can be identified. Surprisingly and unexpectedly, the compounds of this invention satisfy the requirements of an effective and useful photoaffinity probe.